Use of direct oral anticoagulants for venous thromboembolism treatment at extremes of body weight, renal and liver function: an illustrated review.

Direct oral anticoagulants (DOACs) have been a welcome addition to clinical practice due to the practical advantages they confer over traditional anticoagulants. In many countries, DOACs are now used as first-line treatment for the management of venous thromboembolism (VTE). Traditional anticoagulants allow for a degree of individualization, either through monitoring the international normalized ratio in the case of vitamin-K antagonists or through dose titration according to bodyweight in the case of low-molecular-weight heparin. However, the use of fixed doses and removal of the need for routine monitoring has created uncertainty in prescribing DOACs for patients at the extremes of bodyweight, renal function, and patients with liver impairment, who were not well represented in the DOAC licensing clinical trials. The discipline of pharmacokinetics is concerned with the movement of drugs through the body. Although the extremes of bodyweight and renal and liver function will influence the pharmacokinetics of DOACs, are these changes significant enough to affect clinical outcomes of bleeding and thrombosis? In other words, can the fixed-dosing strategy of DOACs accommodate these differences in physiology? In this review, we recap key pharmacokinetic principles for drug dosing; review venous thromboembolism trial and real-world data on patients prescribed DOACs at the extremes of bodyweight, renal function, and liver function; relate this to the pharmacokinetic properties of DOACs; and summarize the state of the field and current unknowns.

Cerebral venous sinus thrombosis and thrombocytopenia after COVID-19 vaccination - A report of two UK cases.

Recent reports have highlighted rare, and sometimes fatal, cases of cerebral venous sinus thrombosis (CVST) and thrombocytopenia following the Vaxzevria vaccine. An underlying immunological mechanism similar to that of spontaneous heparin-induced thrombocytopenia (HIT) is suspected, with the identification of antibodies to platelet factor-4 (PF4), but without previous heparin exposure. This unusual mechanism has significant implications for the management approach used, which differs from usual treatment of CVST. We describe the cases of two young males, who developed severe thrombocytopenia and fatal CVST following the first dose of Vaxzevria. Both presented with a headache, with subsequent rapid neurological deterioration. One patient underwent PF4 antibody testing, which was positive. A rapid vaccination programme is essential in helping to control the COVID-19 pandemic. Hence, it is vital that such COVID-19 vaccine-associated events, which at this stage appear to be very rare, are viewed through this lens. However, some cases have proved fatal. It is critical that clinicians are alerted to the emergence of such events to facilitate appropriate management. Patients presenting with CVST features and thrombocytopenia post-vaccination should undergo PF4 antibody testing and be managed in a similar fashion to HIT, in particular avoiding heparin and platelet transfusions.

Postdischarge venous thromboembolism following hospital admission with COVID-19.

The association of severe coronavirus disease 2019 (COVID-19) with an increased risk of venous thromboembolism (VTE) has resulted in specific guidelines for its prevention and management. The VTE risk appears highest in those with critical care admission. The need for postdischarge thromboprophylaxis remains controversial, which is reflected in conflicting expert guideline recommendations. Our local protocol provides thromboprophylaxis to COVID-19 patients during admission only. We report postdischarge VTE data from an ongoing quality improvement program incorporating root-cause analysis of hospital-associated VTE (HA-VTE). Following 1877 hospital discharges associated with COVID-19, 9 episodes of HA-VTE were diagnosed within 42 days, giving a postdischarge rate of 4.8 per 1000 discharges. Over 2019, following 18 159 discharges associated with a medical admission; there were 56 episodes of HA-VTE within 42 days (3.1 per 1000 discharges). The odds ratio for postdischarge HA-VTE associated with COVID-19 compared with 2019 was 1.6 (95% confidence interval, 0.77-3.1). COVID-19 hospitalization does not appear to increase the risk of postdischarge HA-VTE compared with hospitalization with other acute medical illness. Given that the risk-benefit ratio of postdischarge thromboprophylaxis remains uncertain, randomized controlled trials to evaluate the role of continuing thromboprophylaxis in COVID-19 patients following hospital discharge are required.

Fixed dose rivaroxaban can be used in extremes of bodyweight: A population pharmacokinetic analysis.

BACKGROUND: Emerging safety and efficacy data for rivaroxaban suggest traditional therapy and rivaroxaban are comparable in the morbidly obese. However, real-world data that indicate pharmacokinetic (PK) parameters are comparable at the extremes of body size are lacking. The International Society of Thrombosis and Haemostasis Scientific and Standardisation Committee (ISTH SSC) suggests avoiding the use of direct oral anticoagulants (DOACs) in patients weighing >120 kg or with a body mass index >40 kg/m2 and gives no recommendation on the use of DOACs in those <50 kg. OBJECTIVES: To generate a population PK model to understand the influence of bodyweight on rivaroxaban exposure from clinical practice data. METHOD: Rivaroxaban plasma concentrations and patient characteristics were collated between 2013 and 2018 at King's College Hospital anticoagulation clinic. A population PK model was developed using a nonlinear mixed effects approach and then used to simulate rivaroxaban concentrations at the extremes of bodyweight. RESULTS: A robust population PK model derived from 913 patients weighing between 39 kg and 172 kg was developed. The model included data from n = 86 >120 kg, n = 74 BMI >40 kg/m2 , and n = 30 <50 kg. A one-compartment model with between-subject variability on clearance and a proportional error model best described the data. Creatinine clearance calculated by Cockcroft-Gault, with lean bodyweight as the weight descriptor in this equation, was the most significant covariate influencing rivaroxaban exposure. CONCLUSIONS: Our work demonstrates rivaroxaban can be used at extremes of bodyweight provided renal function is satisfactory. We recommend that the ISTH SSC revises the current guidance with respect to rivaroxaban at extremes of body size.

Annotation: travel and thrombosis.

Travel appears to be a weak risk factor for venous thromboembolism (VTE) and is more relevant for passengers with additional VTE risk factors. The association is not limited to air travel and is related to duration of travel. Life-threatening pulmonary embolism (PE) is rare. There is limited evidence to support interventions, including 'sensible measures', graduated compression stockings (GCS) and low-molecular-weight heparin (LMWH). It is difficult to confidently define a population who would benefit from thromboprophylaxis and no validated risk assessment exists for this purpose. LMWH has traditionally been used for flight thromboprophylaxis but a direct oral anticoagulant (DOAC) would be a more appealing oral option.

What are the difficulties in conducting randomised controlled trials of thromboprophylaxis in myeloma patients and how can we address these? Lessons from apixaban versus LMWH or aspirin as thromboprophylaxis in newly diagnosed multiple myeloma (TiMM) feasibility clinical trial.

Routine thromboprophylaxis (TP) in newly-diagnosed multiple myeloma (NDMM) patients comprises either aspirin for standard risk patients or low molecular weight heparin for high risk patients. Studies using DOACs in cancer patients include few with myeloma. The aim of this feasibility clinical trial was to establish the foundations for creating a multicentre trial and identify any safety concerns with apixaban. Patient perspectives were sought. NDMM patients were stratified according to VTE risk and randomised to either standard TP or apixaban 2.5 mg BD and reviewed every 3 weeks throughout their chemotherapy. Two focus groups were carried out on 2 occasions at King's College Hospital and Guy's Hospital, London. Each lasted an hour, were recorded, transcribed and themes explored using NVivo 11. Ten patients were recruited, 2 considered high risk and received apixaban and 8 standard risk; 4 randomised to aspirin and 4 to apixaban. Five patients and 2 carers participated in the focus groups. There were no major bleeding or VTE events. Patients were not aware of the thrombotic risk associated with cancer. There is a lack of both written and verbal information on this topic. Myeloma patients were happy to be included in more than one trial simultaneously. Our study provides information on the difficulties facing physicians and patients on obtaining evidence of the safety of DOACs in the context of myeloma. Despite patients being happy to co-recruit into thromboprophylaxis trials along with chemotherapy trials this is not current practice.EudraCT Number: 2015-002668-18.

Current challenges and future prospects in oral anticoagulant therapy.

The choice for oral anticoagulant (OAC) therapy was previously limited to the vitamin K antagonists (VKAs). The advent of the direct oral anticoagulants (DOACs) brought with it the expectation that oral anticoagulation would become simpler (with the elimination of routine monitoring and introduction of a fixed-dose anticoagulant), and that the use of VKAs would be slowly phased out. Although DOACs have made anticoagulation more convenient and accessible, we are now faced with what can be described as a tyranny of choice, together with many unanswered questions relating to DOAC use. These include optimal DOAC selection and dosing, use in complex 'real-world' patients, the role for monitoring and issues surrounding adherence. Warfarin remains the anticoagulant of choice in certain scenarios (e.g. metallic heart valves). The future holds much excitement: clinical studies are underway to expand the indications for DOACs and experience continues to grow outside the trials setting.

Increased prevalence of heparin-induced thrombocytopenia in patients with Budd-Chiari syndrome: a retrospective analysis.

BACKGROUND: Budd-Chiari syndrome (BCS) is a rare, potentially fatal disease characterized by hepatic venous outflow tract obstruction. Heparin-induced thrombocytopenia (HIT) is an immune-mediated complication of heparin therapy, with mortality approaching 10%. The reported prevalence of HIT in adults is 0.2-5.2%. Expert consensus through case reports is the only existing evidence of HIT in BCS. To our knowledge, this is the first study to formalize this anecdotal evidence. METHODS: A retrospective analysis was carried out of patients presenting at a tertiary liver centre with acute liver failure because of BCS or BCS as the primary indication for liver transplantation between 2000 and 2013. The prevalence of HIT in the study group was compared with the highest reported prevalence in adult medical patients receiving heparin (5.2%). Mortality, length of stay and liver transplantation rates were also studied. RESULTS: Of 32 BCS patients, 9 (28.1%) developed HIT, significantly higher than the previously reported prevalence of HIT in medical patients (5.2%) (P<0.0001). There was no difference in mortality (P=0.66), length of stay (P=0.58) and liver transplantation rate (P=0.39) between HIT-positive and HIT-negative patients. CONCLUSION: The prevalence of HIT (28.1%) in our cohort of BCS patients is significantly higher than that in the general population (0.2-5.2%). Although this study was not powered to detect outcome differences, as heparin is the mainstay of acute BCS treatment, this represents a significant risk. We recommend a high index of suspicion for HIT in patients with BCS and thrombocytopenia, an appropriate HIT-testing strategy and consideration of direct thrombin inhibitors.